Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting TLR4 signaling may contribute to both side effects. therefore aimed determine if genetic deletion of improves pain. Forty-two female wild-type (WT) 42 Tlr4 null (-/-) BALB/c mice weighing between 18 25 g (10-13 weeks) received a single 270 mg/kg (i.p.) dose irinotecan hydrochloride or vehicle control...

Background and Objectives The most common treatment for opioid dependence is substitution therapy with another such as methadone. methadone dosage individualized but highly variable, program retention rates are low due in part to nonoptimal dosing resulting withdrawal symptoms further heroin craving use. Methadone a substrate the P-glycoprotein transporter, encoded by ABCB1 gene, which regulates central nervous system exposure. This retrospective study aimed investigate influence of genetic...

To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone norhydrocodone, individual cytochrome p450 enzymes involved, predict in vivo hepatic intrinsic clearance via these pathways.

Aims To investigate in a large panel of 50 human liver samples the contribution CYP2C9, CYP2D6, and CYP3A4 to overall formation potent antioestrogen Z‐4‐hydroxy‐tamoxifen, how various genotypes affect its from tamoxifen. Methods The Z‐4‐hydroxy‐tamoxifen 10 µ m tamoxifen was studied microsomes ( n =50), characterized for CYP2B6, CYP2D6 expression, CYP2B6 , CYP2C9 genotype. effect chemical monoclonal antibody inhibitors, supersomes expressing recombinant CYP isoforms also investigated....

Abstract The Taq I A polymorphism (A 1 ) of the dopamine D 2 receptor gene ( DRD2 ), although not a specific predictor opioid dependence, has been strongly associated with high levels prior heroin use and poor treatment outcomes among methadone maintenance patients. aims this study were to confirm these findings via retrospective analysis allele frequency in (n = 46) buprenorphine 25) patients, non‐opioid‐dependent controls 95). Subjects genotyped at locus using PCR amplification followed by...

BACKGROUND AND PURPOSE Emerging evidence implicates a role for toll‐like receptor 4 (TLR4) in the CNS effects of alcohol. The aim current study was to determine whether TLR4–MyD88‐dependent signalling is involved acute behavioural actions alcohol and if can activate TLR4‐downstream MAPK NF‐κB pathways. EXPERIMENTAL APPROACH TLR4 pathway evaluated using antagonist (+)‐naloxone (µ‐opioid receptor‐inactive isomer) mice with null mutations MyD88 genes. Sedation motor impairment induced by single...

Aims Ketamine analgesia is limited by low intrinsic efficacy compounded large interindividual variability in drug responses, possibly due to the heterogeneity concentration. The CYP2B6 * 6 allele associated with substantially reduced ketamine metabolism vitro and, therefore, may affect clearance. Our aims were examine impact of on plasma clearance and adverse effects chronic pain patients. Methods genotypes identified 49 patients who received 24 h continuous subcutaneous infusions ketamine....

Ketamine is primarily metabolized to norketamine by hepatic CYP2B6 and CYP3A4-mediated <i>N</i>-demethylation. However, the relative contribution from each enzyme remains controversial. The <i>CYP2B6*6</i> allele associated with reduced expression activity that may lead interindividual variability in ketamine metabolism. We examined <i>N-</i>demethylation of individual enantiomers using human liver microsomes (HLMs) genotyped for allele, insect cell–expressed recombinant CYP3A4 enzymes,...

Abstract We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4−/−) protected against loss barrier function, indicating that TLR4 is critical tight junction regulation. The current study aimed (i) determine the molecular characteristics junctions wild-type and Tlr4−/− (ii) characterize secretory profile distal colon. Forty-two female 42 weighing between 18 25...

The role of CYP pharmacogenetics in the bioactivation cyclophosphamide is still controversial. Recent clinical studies have suggested a for either CYP2C19 or CYP2B6. aim this study was to clarify these pharmacogenes.We used combined vitro-in vivo approach determine pharmacogenes prodrug 4-hydroxy (4-OHCP). Cyclophosphamide metabolism determined human liver biobank (n= 14) and patients receiving drug treatment lupus nephritis 16)In livers known CYP2B6 genotype protein expression we observed...

Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics different settings. There is evidence OPRM1, mu opioid receptor, and interact affect morphine response opposite ways. This study aimed examine whether a similar gene-gene interaction occurs for...

Given the evidence from retrospective studies indicating that alcohol-dependent patients with homozygous or heterozygous A118G variant of μ-opioid receptor, OPRM1, gene have significantly better outcomes when treated naltrexone; this study examined prospectively in 100 participants prescribed naltrexone for 12 weeks and offered six sessions cognitive-behavioral therapy intervention. Comparisons were made among OPRM1 genotypic groups on several outcome measures. Naltrexone treatment produced...

Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2) and CYP3A co-factor cytochrome reductase (POR) have been studied for effects on tacrolimus disposition....

Objective To examine the association between genetic variability of IL-1B, which encodes for proinflammatory cytokine IL-1β and risk developing opioid dependence. confirm a previous study, we also examined IL-1B polymorphism alcohol Methods Genomic DNA was isolated from 60 opioid-dependent, 99 alcohol-dependent patients healthy nondependent controls. Polymerase chain reaction restriction fragment length were used to determine presence single nucleotide polymorphisms at positions -511, -31...

Tacrolimus (TAC) has a narrow therapeutic index and high interindividual intraindividual pharmacokinetic variability, necessitating drug monitoring to individualize dosage. Recent evidence suggests that intragraft TAC concentrations may better predict transplant outcomes. This study aimed develop method for the quantification of in small biopsy-sized samples rat kidney liver tissue, which could be applied clinical biopsy from recipients.Kidneys livers were harvested Mrp2-deficient TR- Wistar...